An underlying hypothesis of this proposal is that normal cellular protective responses to ionizing radiation can be activated and/or augmented through the administration of chemoprotectants and mitigators, which will be discovered through the comprehensive drug discovery program inherent to this proposal. Tightly linked to this drug discovery program is an animal program, operated through this Animal Core that will provide and develop transgenic and conditional knockout mouse models to assist in discovery and identification of chemoprotectants. Provisions for testing promising chemoprotectants in non-human primates are also described. Transgenic and conditional knockout mice will be used in the discovery of chemoprotectants by: (1) providing model organisms for testing the protectant nature of a number of promising chemicals, (2) by providing a means of discovering chemoprotectants that protect from ionizing radiation damage due to their interaction with biochemical and signaling pathways that are known or are suspected of playing a major role in preventing or mitigating the effects of ionizing radiation, and (3) by providing a means of determining the physiologic function of the newly designed chemo-protector and mediator agents. The Specific Aims of the Animal Core are: (1) Generate transgenic and knockout lines of mice to understand the effects of different chemicals in protecting against radiation injury or in mitigating the effects of ionizing radiation. (2) Provide professional expertise in the design and execution of experiments using transgenic and knockout lines of mice. (3) Procure tissues from specialized genetic mouse lines that are generated by the Animal Core or are acquired by the Animal Core for use by the investigators in the Program. (4) Derive cell lines, including ES cell lines, from mutant mice for use in the in vitro testing and study of chemical protectors and mitigators. (5) Evaluate results involving experimental animals and propose subsequent experimental direction.